Nörodejeneratif Hastalıklarda Yeni Bir Yaklaşım: Mitokondri Hedefli Tedavi

Yıl 2024, Cilt: 11 Sayı: 3, 487 - 493, 30.09.2024

Kübra Çelik , Dilek Taşkıran

https://doi.org/10.34087/cbusbed.1281151

Öz

Mitokondri hücrenin enerji metabolizmasında, oksidatif fosforilasyonda ve hücre ölümünde rol alan temel organeli olup pek çok hastalıkta olduğu gibi nörodejeneratif hastalıkların da patogenezine katkı sağlar. Günümüzde çoğu nörodejeneratif hastalığın etiyopatogenezinde reaktif oksijen ve nitrojen türlerine bağlı oksidatif hasar sorumlu tutulmakla birlikte antioksidan tedaviler bu hasarın önlenmesi ve iyileştirilmesi konusunda yeterli olmamaktadır. Bu nedenle son yıllarda mitokondriyi direkt olarak hedefleyen ve içerisinde biriken farklı farmakolojik ajanlar geliştirilmiş olup birçok nörodejenerasyon hayvan modelinde iyileştirici etkileri görülmüştür. Aynı zamanda bu ajanlardan bazılarının insan klinik çalışmalarında güvenilir ve etkili olduğu kanıtlanmıştır. Bu derlemede, Alzheimer ve Parkinson hastalıkları başta olmak üzere nörodejeneratif hastalıklarda mitokondri disfonksiyonu ve bu hastalıkların tedavisinde etkili olacağı düşünülen mitokondri hedefli tedavi ile ilgili güncel bilgiler tartışılmıştır.

Anahtar Kelimeler

mitokondri, mitokondri hedefli tedavi, nörodejeneratif hastalıklar

A New Approach to Neurodegenerative Diseases: Mitochondria-targeted Treatment

Öz

Mitochondria are the main organelles involved in the energy metabolism of the cell, oxidative phosphorylation and cell death, and contribute to the pathogenesis of many diseases as well as neurodegenerative diseases. Although oxidative damage due to reactive oxygen and nitrogen species is blamed in the etiopathogenesis of several neurodegenerative diseases, antioxidant treatments are not sufficient in preventing and curing this damage. Therefore, in recent years, various pharmacological agents that directly target and accumulate in the mitochondria have been developed, and their healing effects have been observed in many neurodegeneration animal models. Also, some of these agents have been found reliable and effective in human clinical trials. In this review, current knowledge about mitochondrial dysfunction in neurodegenerative diseases, especially Alzheimer’s and Parkinson diseases and mitochondria targeted therapy, which is thought to be efficient in the treatment of these diseases, are discussed.

Anahtar Kelimeler

mitochondria, mitochondria targeted therapy, neurodegenerative diseases

Kaynakça

• 1. Johnson, J., Mercado-Ayon, E., Mercado-Ayon, Y., Dong, Y. N., Halawani, S., Ngaba, L., Lynch, D. R. Mitochondrial dysfunction in the development and progression of neurodegenerative diseases. Archives of biochemistry and biophysics, 2021,702, 108698.
• 2. Mani, S., Swargiary, G., Ralph, S. J. Targeting the redox imbalance in mitochondria: A novel mode for cancer therapy. Mitochondrion, 2022, 62, 50-73.
• 3. Tang, Y., Wang, L., Qin, J., Lu, Y., Shen, H. M., & Chen, H. B. Targeting mitophagy to promote apoptosis is a potential therapeutic strategy for cancer. Autophagy, 2023 19(3), 1031-1033.
• 4. Li, W., & Xu, X. Advances in mitophagy and mitochondrial apoptosis pathway-related drugs in glioblastoma treatment. Frontiers in Pharmacology, 2023,14, 1211719.
• 5. Xu, J., Shamul, J. G., Kwizera, E. A., He, X. Recent advancements in mitochondria-targeted nanoparticle drug delivery for cancer therapy. Nanomaterials, 2022, 12(5), 743.
• 6. Johnson, J., Mercado-Ayon, E., Mercado-Ayon, Y., Dong, Y. N., Halawani, S., Ngaba, L., & Lynch, D. R. Mitochondrial dysfunction in the development and progression of neurodegenerative diseases. Archives of biochemistry and biophysics, 2021, 702, 108698.
• 7. Chandel NS. Mitochondria. Cold Spring Harb Perspect Biol 2021, 13(3), a040543.
• 8. Smith, A. L., Whitehall, J. C., & Greaves, L. C. Mitochondrial DNA mutations in aging and cancer. Molecular Oncology, 2022,16(18), 3276-3294.
• 9. Palade GE. The fine structure of mitochondria. Anat Rec 1952, 114(3), 427-451.
• 10. Protasoni, M., Zeviani, M. Mitochondrial structure and bioenergetics in normal and disease conditions. International journal of molecular sciences, 2021,22(2), 586.
• 11. Taylor, D. F., Bishop, D. J. Transcription factor movement and exercise-induced mitochondrial biogenesis in human skeletal muscle: Current knowledge and future perspectives. International Journal of Molecular Sciences, 2022,23(3), 1517.
• 12. Shah, M., Chacko, L. A., Joseph, J. P., Ananthanarayanan, V. Mitochondrial dynamics, positioning and function mediated by cytoskeletal interactions. Cellular and Molecular Life Sciences, 2021,78, 3969-3986.
• 13. Monzel, A. S., Enríquez, J. A., Picard, M. Multifaceted mitochondria: moving mitochondrial science beyond function and dysfunction. Nature metabolism, 2023,5(4), 546-562.
• 14. Adebayo, M., Singh, S., Singh, A. P., Dasgupta, S. Mitochondrial fusion and fission: The fine-tune balance for cellular homeostasis. FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 2021,35(6), e21620.
• 15. Quan, Y., Xin, Y., Tian, G., Zhou, J.,Liu, X. Mitochondrial ROS‐Modulated mtDNA: a potential target for cardiac aging. Oxidative medicine and cellular longevity, 2020(1), 9423593.
• 16. Alabduladhem, T. O., Bordoni, B. Physiology, krebs cycle. In StatPearls,2022, StatPearls Publishing.
• 17. Nolfi-Donegan, D., Braganza, A.,Shiva, S. Mitochondrial electron transport chain: Oxidative phosphorylation, oxidant production, and methods of measurement. Redox biology, 2020,37, 101674.
• 18. Andrés, C. M. C., Pérez de la Lastra, J. M., Andrés Juan, C., Plou, F. J., Pérez-Lebeña, E. Superoxide anion chemistry- Its role at the core of the innate immunity. International journal of molecular sciences, 2023,24(3), 1841.
• 19. Rey, F., Ottolenghi, S., Zuccotti, G. V., Samaja, M., Carelli, S. Mitochondrial dysfunctions in neurodegenerative diseases: Role in disease pathogenesis, strategies for analysis and therapeutic prospects. Neural Regeneration Research, 2022, 17(4), 754-758.
• 20. Park H, Ellis AC. Dietary Antioxidants and Parkinson's Disease. Antioxidants 2020; 9(7), 570.
• 21. Gasmi A, Peana M, Arshad M, et.al. Krebs cycle: activators, inhibitors and their roles in the modulation of carcinogenesis. Arch Toxicol 2021; 1-18.
• 22. Angelova, P.R., Esteras, N.,Abramov, A. Y. Mitochondria and lipid peroxidation in the mechanism of neurodegeneration: Finding ways for prevention. Medicinal Research Reviews, 2021, 41(2), 770-784.
• 23. Huang, Z., Chen, Y., Zhang, Y. Mitochondrial reactive oxygen species cause major oxidative mitochondrial DNA damages and repair pathways. Journal of biosciences, 2020, 45(1), 84.
• 24. Boone, C., Lewis, S. C. Bridging lipid metabolism and mitochondrial genome maintenance. Journal of Biological Chemistry, 2024, 300(8).
• 25. Palma, F. R., Gantner, B. N., Sakiyama, M. J., Kayzuka, C., Shukla, S., Lacchini, R., Bonini, M. G. ROS production by mitochondria: function or dysfunction?. Oncogene, 2024 43(5), 295-303.
• 26. Grel, H., Woznica, D., Ratajczak, K., Kalwarczyk, E., Anchimowicz, J., Switlik, W., Jakiela, S. Mitochondrial dynamics in neurodegenerative diseases: unraveling the role of fusion and fission processes. International Journal of Molecular Sciences, 2023, 24(17), 13033.
• 27. Gao, X. Y., Yang, T., Gu, Y.,Sun, X. H. Mitochondrial dysfunction in Parkinson’s disease: from mechanistic insights to therapy. Frontiers in aging neuroscience, 2022 14, 885500.
• 28. Bhatia, S., Rawal, R., Sharma, P., Singh, T., Singh, M., Singh, V.Mitochondrial dysfunction in Alzheimer’s disease: opportunities for drug development. Current Neuropharmacology, 2022,20(4), 675.
• 29. Sharma, A., Behl, T., Sharma, L., Aelya, L.,Bungau, S. Mitochondrial dysfunction in Huntington’s disease: pathogenesis and therapeutic opportunities. Current Drug Targets, 2021,22(14), 1637-1667.
• 30. Xiao Y, Karam C, Yi J, et. al. ROS-related mitochondrial dysfunction in skeletal muscle of an ALS mouse model during the disease progression. Pharmacol Res , 2018, 138, 25-36.
• 31. Horan K, The role of mitochondrial dysfunction in the pathogenesis of tauopathies. Electronic Thess or Dissertation, Case Wester Reserve University. 2021.
• 32. Trease A, George J, Emanuel K et.al. Tau protein preferentially associates with synaptic mitochondria in a mouse model of taupathy, 2021.
• 33. Guha S, Fischer S, Johnson GVW et.al. Tauopathy-associated tau modifications selectively impact neurodegeneration and mitophagy in a novel C. Elegans single-copy transgenic model. Mol Neurodegeneration 2020, 15,65.
• 34. Esteras N, Abramov AY. Mitochondrial calcium deregulation in the mechanism of beta-amyloid and tau pathology. Cells. 2020,9[9], 2135.
• 35. Picca, A., Guerra, F., Calvani, R., Coelho-Júnior, H. J., Leeuwenburgh, C., Bucci, C.,Marzetti, E.The contribution of mitochondrial DNA alterations to aging, cancer, and neurodegeneration. Experimental Gerontology, 2023,178, 112203.
• 36. Song, R., Chen, H., Zhan, R., Han, M., Zhao, L., Shen, X. Vitamin E protects dopaminergic neurons against manganese-induced neurotoxicity through stimulation of CHRM1 and KCNJ4. Journal of Trace Elements in Medicine and Biology, 2024,81, 127326.
• 37. Park H, W Park CG, Park M, et.al. Intrastriatal administration of coenzyme Q10 enhances neuroprotection in a Parkinson’s disease rat model. Sci Rep 2020,10(1), 1-12.
• 38. Szeto HH. Mitochondria-targeted cytoprotective peptides for ischemia-reperfusion injury. Antioxid Redox Signal 2008; 10(3), 601-620.
• 39. Polyzos A, Holt A, Brown C, et.al Mitochondrial targeting of XJB-5-131 attenuates or improves pathophysiology in HdhQ150 animals with well-developed disease phenotypes. Hum Mol Genet 2016, 25(9), 1792-1802.
• 40. Xu, J., Du, W., Zhao, Y., Lim, K., Lu, L., Zhang, C., Li, L. Mitochondria targeting drugs for neurodegenerative diseases—Design, mechanism and application. Acta Pharmaceutica Sinica B, 2022, 12(6), 2778-2789.
• 41. Gan L, Wang Z, Si J, Zhou R, Sun C, Liu Y, Ye Y, Zhang Y, Liu Z, Zhang, H. Protective effect of mitochondrial-targeted antioxidant MitoQ against iron ion 56Fe radiation-induced brain injury in mice. Toxicol Appl Pharmacol 2018, 341, 1-7.
• 42. Skulachev VP. Mitochondria-targeted antioxidants as promising drugs for treatment of age-related brain diseases. J Alzheimer's Dis 2012, 28[2], 283-289.
• 43. Fields, M., Marcuzzi, A., Gonelli, A., Celeghini, C., Maximova, N.,Rimondi, E. Mitochondria-targeted antioxidants, an innovative class of antioxidant compounds for neurodegenerative diseases: perspectives and limitations. International journal of molecular sciences, 2023, 24(4), 3739.
• 44. Almikhlafi, M. A., Karami, M. M., Jana, A., Alqurashi, T. M., Majrashi, M., Alghamdi, B. S., Ashraf, G. M. Mitochondrial medicine: A promising therapeutic option against various neurodegenerative disorders. Current Neuropharmacology, 2023,21(5), 1165.
• 45. Wu, Y. Y., Kuo, H. C. Functional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases. Journal of Biomedical Science, 2020,27(1), 49.
• 46. Tai Y., Chen J., Tao Z., & Ren, J. Non-coding RNAs: new players in mitophagy and neurodegeneration. Neurochemistry International, 2022,152, 105253.
• 47. Saikia, B. J., Bhardwaj, J., Paul, S., Sharma, S., Neog, A., Paul, S. R., Binukumar, B. K. Understanding the roles and regulation of mitochondrial microRNAs (MitomiRs) in neurodegenerative diseases: Current status and advances. Mechanisms of Ageing and Development, 2023, 213, 111838.
• 48. Kuo, M. C., Liu, S. C. H., Hsu, Y. F., Wu, R. M. The role of noncoding RNAs in Parkinson’s disease: biomarkers and associations with pathogenic pathways. Journal of biomedical science, 2021, 28(1), 78.
• 49. Wu YY., Kuo HC. Functional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases. Journal of Biomedical Science, 2020, 27, 1-23.
• 50. Zhang M., He P.,Bian Z. Long noncoding RNAs in neurodegenerative diseases: pathogenesis and potential implications as clinical biomarkers. Frontiers in Molecular Neuroscience, 2021,14, 685143.
• 51. Luo Y., Qiu W., Wu B.,Fang F. An overview of mesenchymal stem cell-based therapy mediated by noncoding RNAs in the treatment of neurodegenerative diseases. Stem cell reviews and reports, 2021,1-17.
• 52. Saikia, B. J., Bhardwaj, J., Paul, S., Sharma, S., Neog, A., Paul, S. R., Binukumar, B. K. Understanding the roles and regulation of mitochondrial microRNAs (MitomiRs) in neurodegenerative diseases: Current status and advances. Mechanisms of Ageing and Development, 2023, 213, 11183.
• 53. Williamson J, Hughes CM, Cobley JN, et.al. The mitochondria-targeted antioxidant MitoQ, attenuates exercise-induced mitochondrial DNA damage. Redox Biol 2020; 36, 101673.
• 54. Grünewald A, Kumar KR, Sue CM. New insights into the complex role of mitochondria in Parkinson’s disease. Prog Neurobiol 2019; 177,73-93